U.S. patent application number 15/971883 was filed with the patent office on 2018-11-08 for implantable cardiac devices and methods for delivering low energy, pain-free defibrillation signals for ventricular arrhythmias.
The applicant listed for this patent is UNIVERSITY OF UTAH RESEARCH FOUNDATION. Invention is credited to Derek J. Dosdall, Ravi Ranjan.
Application Number | 20180318594 15/971883 |
Document ID | / |
Family ID | 64014030 |
Filed Date | 2018-11-08 |
United States Patent
Application |
20180318594 |
Kind Code |
A1 |
Dosdall; Derek J. ; et
al. |
November 8, 2018 |
IMPLANTABLE CARDIAC DEVICES AND METHODS FOR DELIVERING LOW ENERGY,
PAIN-FREE DEFIBRILLATION SIGNALS FOR VENTRICULAR ARRHYTHMIAS
Abstract
An implantable cardioverter defibrillator (ICD) and methods of
detection and treatment of dangerous and life-threatening heart
rhythms by delivering real-time, customized low-energy pacing
pulses to specific anatomy in the heart. The ICD includes a power
source, a controller, powered by the power source, including an
electronic processor, a memory, and a signal generator. The ICD
also includes a lead coupled to the controller and an electrode
that is in electrical communication with a His-bundle of a
patient's heart. The ICD detects a ventricular arrhythmia of the
patient's heart using the controller, and is configured to provide
a pulsed defibrillation signal to the electrode to terminate the
ventricular arrhythmia.
Inventors: |
Dosdall; Derek J.;
(Centerville, UT) ; Ranjan; Ravi; (Salt Lake City,
UT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
UNIVERSITY OF UTAH RESEARCH FOUNDATION |
Salt Lake City |
UT |
US |
|
|
Family ID: |
64014030 |
Appl. No.: |
15/971883 |
Filed: |
May 4, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62501693 |
May 4, 2017 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 1/3702 20130101;
A61N 1/39622 20170801; A61N 1/3987 20130101; A61N 1/3937
20130101 |
International
Class: |
A61N 1/39 20060101
A61N001/39 |
Goverment Interests
STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH OR DEVELOPMENT
[0002] This invention was made with government support under R01
HL128752 awarded by the National Institutes of Health. The
government has certain rights in the invention.
Claims
1. An implantable cardioverter-defibrillator comprising: a power
source; a controller, powered by the power source, including an
electronic processor, a memory, and a pulse generator; a His-bundle
lead coupled to the controller and an electrode that is in
electrical contact with the His-bundle of a patient's heart; and a
sensing lead coupled to the controller and in electrical
communication with the patient's heart, the sensing lead configured
to detect electrical signals generated by the patient's heart, and
wherein the controller is configured to receive the electrical
signals provided by the sensing lead, process the electrical
signals to determine if ventricular fibrillation is present, if
ventricular fibrillation is detected on the electrical signals,
transmit instructions to the pulse generator to deliver a pulsed
defibrillation signal to the electrode to terminate the ventricular
fibrillation.
2. The implantable cardioverter defibrillator of claim 1, wherein
the pulsed defibrillation signal is based on a cycle length of the
ventricular fibrillation.
3. The implantable cardioverter defibrillator of claim 2, wherein
the pulsed defibrillation signal provides 10-30 pacing pulses at
80%-105% of the cycle length of the ventricular fibrillation.
4. The implantable cardioverter defibrillator of claim 3, further
comprising a capacitor circuit in communication with the
controller.
5. The implantable cardioverter defibrillator of claim 4, wherein
the capacitor circuit is configured to deliver a defibrillation
shock to the electrode if the ventricular fibrillation remains
present after the pulsed defibrillation signal fails to return the
patient's heart to a normal sinus rhythm.
6. The implantable cardioverter defibrillator of claim 4, wherein
the capacitor circuit is configured to deliver a defibrillation
shock to the electrode if the ventricular fibrillation is not
terminated after the pulsed defibrillation signal is applied to the
electrode.
7. The implantable cardioverter defibrillator of claim 6, wherein
the capacitor circuit is discharged if the ventricular fibrillation
is terminated.
8. The implantable cardioverter defibrillator of claim 1, further
comprising a detector circuit coupled to the sensing lead.
9. A method for ventricular defibrillation, the method comprising:
detecting the presence of ventricular fibrillation in a patient via
an implantable cardioverter-defibrillator including a controller
electrically coupled to an electrode that is in electrical
communication with a His-bundle of a patient's heart; determining,
via the controller, a ventricular fibrillation characteristic of a
signal generated by the patient's heart; determining, via the
controller, a pulsed defibrillation signal including a set of
pacing pulse characteristics based on the ventricular fibrillation
characteristic; and delivering the pulsed defibrillation signal
from the controller to the electrode in order to terminate the
ventricular fibrillation.
10. The method of claim 9, wherein the ventricular fibrillation
characteristic is based on a cycle length of the ventricular
fibrillation signal.
11. The method of claim 10, wherein the pulsed defibrillation
signal provides 10-30 pacing pulses at 80%-105% of the cycle length
of the ventricular fibrillation.
12. The method of claim 10, wherein the signal includes about 10 to
about 30 small pulses at about 90% of the cycle length.
13. A method of treating a cardiac arrhythmia, the method
comprising: detecting, with an implanted device, a cardiac
arrhythmia in a patient's heart; determining a characteristic of
the cardiac arrhythmia; determining a signal to apply to the
patient's heart, the signal including a set of timed small pulses
based on the characteristic of the cardiac arrhythmia; and
delivering the signal from the implanted device to an electrode in
contact with a His-bundle of the heart to terminate the cardiac
arrhythmia.
14. The method of claim 13, wherein the cardiac arrhythmia is
characteristic of ventricular fibrillation.
15. The method of claim 14, wherein the characteristic is based on
a cycle length of the ventricular fibrillation.
16. The method of claim 15, wherein the signal includes about 10 to
about 30 small pulses at about 80% to about 105% of the cycle
length.
17. The method of claim 15, wherein the signal includes about 5 to
about 30 small pulses at about 50% to about 105% of the cycle
length.
18. The method of claim 15, wherein the signal includes about 10 to
about 30 small pulses at about 90% of the cycle length.
Description
CROSS-REFERENCE TO RELATED APPLICATION(S)
[0001] This application is a non-provisional of and claims the
benefit of U.S. Provisional Patent Application Ser. No. 62/501,693,
filed on May 4, 2017, the entire contents of which are incorporated
herein by reference.
BACKGROUND OF THE INVENTION
[0003] Cardiovascular disease is the leading cause of death in most
developed countries in the world. About half of all deaths from
coronary heart disease are sudden and unexpected, regardless of the
underlying disease. Approximately one million individuals in the
U.S. develop conditions each year that place them at high risk for
sudden cardiac death (SCD). About 450,000 SCDs occur each year
among U.S. adults. Sudden Cardiac Arrest (SCA), the cause of SCD,
is fatal in approximately 95% of cases. SCA often results from
ventricular fibrillation (VF), which causes cardiac output to
decrease nearly to zero, a level that causes irreversible damage to
the brain and other organs within 10 min or less. Related to this
fact, the odds of surviving SCA decrease approximately 10% for
every minute the individual remains in VF before defibrillation is
successfully performed. Patients at high risk for SCD may be
implanted with an implantable cardioverter defibrillator (ICD) to
provide life-saving defibrillation shocks in the event of the onset
of a life-threatening cardiac arrhythmia. Approximately 150,000
patients receive ICD implantations each year in the U.S.
[0004] Current ICDs use high-energy (25-35 J) shocks to terminate
VF. While large truncated exponential biphasic shocks used by
modern devices are effective at terminating VF, the high current
density surrounding shocking electrodes may cause tissue damage
that leads to increased morbidity and mortality. This damage may be
caused by electroporation, which leads to conduction disturbances,
tissue stunning, necrosis, and compromised cardiac function. ICD
shocks have been associated with elevated troponin I levels, a
well-known marker of cardiac cell death. ICD patients that receive
shocks are at an increased risk of death, even when shocks were
delivered inappropriately for causes other than life-threatening
arrhythmias. However, there is no increase in mortality risk in
patients that received antitachycardia pacing but no shocks.
[0005] Severe mental distress and lower quality of life scores
accompany many patients that receive defibrillation shocks. If a
patient does not lose consciousness before a shock is delivered,
large energy shocks cause severe pain. While ICD defibrillation
shock strengths are often set at maximum levels of 35 J, shocks as
low as 0.4 J are reported as painful. Inappropriate shocks are
delivered to 11-13% of patients and the shocks are often delivered
without warning. These patients are at increased risk for anxiety,
stress, and possibly post-traumatic stress disorder.
[0006] ICDs charge a large capacitor to deliver defibrillation
shocks, often up to hundreds of volts. Patients that receive
multiple high-energy shocks deplete the battery of the ICD more
rapidly, requiring expensive and invasive device replacement
surgery. Development of reliable low energy defibrillation
techniques will reduce the device size and prolong the battery
life.
[0007] ICDs do not prevent the arrhythmias from occurring, but
rather rapidly detect and treat the arrhythmias using electrical
stimulation. Since the introduction of the ICD more than three
decades ago, numerous improvements have been made to lower the
energy required for cardioversion. Improvements to battery life and
integrated electronics have shrunk the size of ICDs while
increasing the longevity of the devices. Antitachycardia pacing
(ATP) for ventricular tachycardia has reduced the number of shocks
given for monomorphic VT episodes. However, ATP is not effective
for VF. Biphasic shocks reduce the energy requirements and increase
the success rates of defibrillation shocks. Alternate waveform
shapes have had limited success in lowering defibrillation
thresholds (DFTs), but have not been widely adopted and require
shocks of sufficient amplitude that they cause damage and pain.
[0008] The critical mass theory of defibrillation states that for a
defibrillation shock to be successful, a shock must render a
critical mass (usually 75-90% of the ventricles) of the ventricular
tissue unexcitable by activation or extension of the refractory
period. Capturing large sections of cardiac tissue at sites distant
from shocking electrodes is necessary to capture a critical mass of
the heart and to terminate reentrant circuits that perpetuate VF.
Cardiac mapping efforts during defibrillation have demonstrated
that defibrillation attempts using a right ventricular electrode
often fail because waves of activation emerge from the left
ventricular apex region. This area of the left ventricle often has
relatively low current density during the defibrillation shock.
Several studies have explored the use of an auxiliary shock
delivered to the LV electrode. Other studies have included the LV
electrode as an additional path for current in parallel with other
standard clinical locations. Since the LV electrode effectively
spreads current into this area of low current density, DFTs drop
significantly. While these techniques have lowered DFTs by as much
as 50% or more, the DFTs are often still an order of magnitude
above the pain threshold. Sequential pulses delivered through
multiple pathways have not gained clinical acceptance due to
additional complexity and risk associated with implantation of
additional leads.
[0009] There has been a resurgence of interest and research into
low energy multi-pulse and high frequency defibrillation
techniques. These techniques generally fall into one of two
categories: 1) A series of pacing pulses or low energy shocks
delivered near or just below the intrinsic VF cycle length that
progressively capture a larger and larger region of fibrillating
tissue until VF is halted.22, 52-61 or 2) High frequency (50-1000
Hz) stimulation that blocks all activation in a critical mass so
that reentrant circuits are disrupted and VF halts.
[0010] As with standard defibrillation shocks, low energy
defibrillation techniques rely on far field virtual electrode
polarization to create secondary sources that disrupt reentrant
circuits to terminate VF. Traditional defibrillation shocks require
a minimum field gradient of 2.7-10.9 V/cm throughout the heart for
successful defibrillation. Intracardiac shocking coils, as used by
ICDs, do not create an even field distribution throughout the
heart. High current densities near shocking coils lead to field
gradients more than 20 times the field gradient experienced by
regions of the heart far from the shocking coils. While the field
gradients required for multi-pulse techniques may be as low as 250
mV/cm, to create this field strength at sites distant from the
shocking electrodes, much higher field gradients are required close
to the shocking coils. Low energy multi-pulse techniques have been
effective in simulations with even field gradients and in
experimental configurations with rabbit or guinea pig ventricles or
canine atria, but the energy required to defibrillate large,
fibrillating ventricles with secondary sources at sites far from
the stimulating electrodes will require substantial increases in
energy and field gradient to create virtual electrodes at remote
sites. Successful demonstration of low energy multi-pulse
techniques in large hearts may prove difficult because direct local
capture leads to a limited region of captured tissue, much smaller
than a critical mass of the heart. While shocks from ICDs are the
only effective therapy for VF, shocks may cause damage to tissue
surrounding intracardiac electrodes leading to increased risk of
arrhythmia or death. While the extent of the damage caused by
shocks is controversial, shocks delivered while patients are
conscious result in pain, anxiety, and lower quality of life
measures.
SUMMARY OF THE INVENTION
[0011] The Purkinje system is a specialized conduction system that
has been implicated as a source of idiopathic VF and selective
radio frequency ablation of the Purkinje system has been used
effectively to terminate and prevent idiopathic VT and VF. Studies
have demonstrated that the Purkinje fiber system also may be
responsible for the onset of arrhythmias during both ischemia and
reperfusion, and that congestive heart failure (HF) leads to
changes in the Purkinje cells that may make them more prone to
arrhythmogenesis. Recent studies have demonstrated that radio
frequency ablation of the endocardial posterior papillary muscle
and the left ventricular posteroseptal region reduced the
inducibility of VF in dogs.
[0012] Recent work has demonstrated that the Purkinje system plays
an active role in the maintenance of VF. Mapping of the endocardium
of isolated dog hearts showed that the Purkinje system plays an
integral role in reentrant activity with the working myocardium and
that focal activity in the Purkinje system initiates VF wavefronts.
Chemical ablation of the Purkinje system led to slowing of VF
activation rate and early spontaneous termination of VF. In later
VF, a pattern of activation emerges during which the entire
endocardium activates quickly through focal activity in the
Purkinje system without activity on the endocardium between each
cycle.
[0013] The Purkinje system has also been shown to be a possible
source of activation leading to defibrillation shock failure when
shocks are given near the DFT. DFT strength shocks induce rapid
firing in the Purkinje system that may lead to shock failure.
Purkinje activations have been detected before or during the
postshock activation cycles in pig and dog hearts. Purkinje fibers
and the intratrabecular gaps in which Purkinje fibers are found are
common sites of virtual electrode effects, and thus are easily
excited by shocks even when the underlying myocardium is not
activated.
[0014] A recent study demonstrated that the His bundle activation
rate was similar to that observed near the distal Purkinje fibers
in prolonged VF. The study utilized isolated rabbit hearts (n=12)
in which an 8.times.8 electrode array with 0.3 mm spacing was
placed directly over the His bundle of isolated, perfused rabbit
hearts. VF was induced with 50 Hz burst pacing, and perfusion was
terminated. Shortly after VF onset, the working myocardium had a
higher activation rate than the His bundle, but by the third minute
of VF, the His activation rate was higher than that of the working
myocardium (see FIG. 7). A repeated measures ANOVA demonstrated
that the working myocardium activation rate decreased over time,
while the His bundle activation rate did not change significantly
over 8 minutes of VF. This behavior has been shown as an activation
rate gradient that is observed in rabbits, dogs, and human hearts
as the Purkinje system continues to activate rapidly while the
working myocardium becomes ischemic and the activation rate slows
away from the Purkinje-myocardial junctions. This study
demonstrated that the His bundle exhibits similar activation
patterns during VF, which indicates that the Purkinje system and
His bundle remain electrically linked during VF and that pacing and
capture of the His bundle will lead to capture of the Purkinje
system during VF.
[0015] While there have been modeling or small animal heart studies
that suggest that stimulating the Purkinje system during
arrhythmias may lead to termination of the arrhythmias or reduction
in energy required for termination, one obstacle to the clinical
implementation of these techniques has been the lack of a
clinically relevant method for stimulating the Purkinje system in
vivo. Improved methods for pacing without causing ventricular
dyssynchrony has driven a surge in research for directly pacing the
ventricular conduction system.
[0016] Pacing the His bundle can be performed during an EP study
with a steerable catheter placed on the high right ventricular
septum. Recently, there have been several groups that have
performed studies to validate techniques for placing a permanent
pacing lead on the His bundle for chronic pacing applications. A
small gauge steerable lead in conjunction with a steerable sheath
have been positioned and fixed in location over the His bundle.
Direct His bundle or paraHisian pacing leads to more synchronous
contractions than a conventional right ventricular apical pacing.
Of the patients that undergo dual lead implantation for cardiac
resynchronization therapy (CRT), 30-40% of them do not show
improvement in LV remodeling and/or reduced mortality. Some
patients that are not candidates for traditional CRT therapy
benefit from direct His bundle pacing. The end result of these
studies is that permanent direct Hisian or paraHisian pacing
techniques are gaining acceptance clinically and leads that are
facilitate direct His pacing are commercially available.
[0017] According to an embodiment, the present invention provides
an implantable cardioverter defibrillator (ICD) including a power
source, a controller, powered by the power source, including an
electronic processor, a memory, and a signal generator. The ICD
also includes a lead coupled to the controller and an electrode
that is in electrical communication with a His-bundle of a
patient's heart. The ICD detects a ventricular arrhythmia of the
patient's heart using the controller, and is configured to provide
a pulsed defibrillation signal to the electrode to terminate the
ventricular arrhythmia.
[0018] According to another embodiment, the present invention
provides a method for ventricular defibrillation including
detecting the presence of ventricular fibrillation in a patient via
an implantable cardioverter-defibrillator having a controller
electrically coupled to an electrode that is in electrical
communication with a ventricular specialized conduction system of a
patient's heart. The method also includes determining, via the
controller, a ventricular fibrillation characteristic of a signal
generated by the patient's heart, and determining, via the
controller, a pulsed defibrillation signal including set of pacing
pulse characteristics based on the ventricular fibrillation
characteristic. Finally, the method includes delivering the pulsed
defibrillation signal from the controller to the electrode in order
to terminate the ventricular fibrillation.
[0019] According to yet another embodiment, the invention provides
a method of treating a cardiac arrhythmia. The method comprises
detecting, with an implanted device, a cardiac arrhythmia in a
patient's heart, determining a characteristic of the cardiac
arrhythmia, determining a signal to apply to the patient's heart,
the signal including a set of timed small pulses based on the
characteristic of the cardiac arrhythmia, and delivering the signal
from the implanted device to an electrode in contact with a
ventricular specialized conduction system of the heart to terminate
the cardiac arrhythmia.
[0020] In a further embodiment, the invention provides an
implantable cardioverter-defibrillator comprising a power source, a
controller, powered by the power source, including an electronic
processor, a memory, and a pulse generator, a His-bundle lead
coupled to the controller and an electrode that is in electrical
contact with the His-bundle of a patient's heart, and a sensing
lead coupled to the controller and in electrical communication with
the patient's heart, the sensing lead configured to detect
electrical signals generated by the patient's heart. The controller
is configured to receive the electrical signals provided by the
sensing lead, process the electrical signals to determine if
ventricular fibrillation is present, if ventricular fibrillation is
detected on the electrical signals, transmit instructions to the
pulse generator to deliver a pulsed defibrillation signal to the
electrode to terminate the ventricular fibrillation.
[0021] Other features and aspects of the invention will become
apparent by consideration of the following detailed description and
accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 is a representation of an implantable cardioverter
defibrillator having a lead disposed within a patient's heart.
[0023] FIG. 2 illustrates a block diagram of the ICD of FIG. 1.
[0024] FIG. 3A is a flow chart illustrating a method for treating a
cardiac arrhythmias using the ICD of FIG. 1.
[0025] FIG. 3B is a flow chart illustrating a method for
terminating ventricular arrhythmias using the ICD of FIG. 1.
[0026] FIG. 4 is a flow chart of a method for determining a
characteristic of ventricular fibrillation.
[0027] FIG. 5 is a flow chart of a process for terminating
ventricular fibrillation using the ICD of FIG. 1.
[0028] FIG. 6 is an exemplary electrocardiogram depicting
implementation of the process of FIG. 3.
[0029] FIG. 7 is a chart that illustrates that an activation rate
gradient develops between the His bundle and the underlying
ventricular myocardium (VM) as VF progresses. At VF onset, the VM
activation rate is higher than the His bundle activation rate. From
the 3rd minute of VF on, the His bundle activation rate is faster
than that of the VM. Significance shown with * for p<0.05 with
Bonferroni-Holm correction.
[0030] FIG. 8 illustrates microelectrode recordings from a Purkinje
fiber (top trace) and adjacent working myocardium (lower trace)
during VF in an isolated canine heart. Horizontal bar at the bottom
shows 500 ms. The Purkinje impalement has a more notable spike and
dome.
[0031] FIG. 9 illustrates that the VF activation rate was detected
for 13 cycles (mean activation rate=48.4 ms) followed by a pacing
train delivered at 90% of the mean activation rate (pulse every
43.5 ms). Following approximately 10 activation cycles, the pacing
captures a section of local myocardium.
[0032] FIG. 10 illustrates an array placed over the His bundle of
an isolated rabbit heart. A strong ventricular, His, and atrial
signals were recorded during sinus rhythm from the 3 regions of the
plaque shown in red, green, and blue, respectively. Electrograms at
sites 1, 2, and 3 are shown in FIG. 11.
[0033] FIG. 11 illustrates a pseudo ECG, unipolar electrogram (from
site 2 in FIG. 10), and 3 Laplacian recordings (from sites 1, 2,
and 3 in FIG. 10) during sinus and VF. Each recording was 500 ms in
duration. The unipole at site 2 shows ventricular (red arrows), His
bundle (green arrows), and atrial (blue arrows) deflection, while
the Laplacians isolate the strongest local signal and eliminate far
field signals. During VF, it is difficult to distinguish different
activation types with the unipolar signal, but the Laplacians
facilitate waveform identification.
[0034] FIG. 12 illustrates pacing the His bundle during VF with 2
mA leads to Purkinje and myocardial capture. Pacing artifacts
(purple lines), His-Purkinje activations (green arrows), and
myocardial activations (red arrows) are shown. Horizontal bar shows
100 ms. (A) Laplacian electrogram and (B) its temporal derivative
at a site 1.2 mm from the pacing site shows both His and myocardial
capture. (C) Laplacian and (D) its temporal derivative at a site
1.5 cm from pacing site demonstrate propagation of both the
Purkinje potential and myocardial activation during VF.
[0035] FIG. 13 illustrates His bundle pacing leads to His,
Purkinje, and ventricular myocardial capture as well as VF
termination. Electrogram recordings from an electrode near the His
pacing site (0.3 mm away), from a separate plaque located on the
apical RV free wall, and from a pseudo-ECG from an isolated rabbit
heart in perfused VF. Each recording is 500 ms in duration. The His
activation rate was detected and 30 pacing pulses were delivered at
90% of the His VF cycle length. Ventricular myocardial (V), His
bundle (H), atrial (A), Purkinje activations (P), and stimulation
pacing (S) are marked. Immediately after beginning pacing (Early
Pacing), there is no evidence of His, Purkinje, nor myocardial
capture. After approximately 20 pacing cycles (Late Pacing), His
capture occurs almost immediately following the pacing stimulus
with 1:1 ventricular activations. On the free wall, there is a
repeatable delay before Purkinje activation, followed by a phase
locked myocardial activation. Myocardial activation was earlier at
the free wall than near the His pacing site, which is consistent
with activation proceeding from the His bundle to the Purkinje
fibers, to the working myocardium near the Purkinje fibers, and
finally to the myocardium near the His pacing site. After
termination of pacing, VF is terminated, although there was a
period of AV conduction block or delay before sinus rhythm
recommenced.
[0036] FIG. 14 illustrates paraHisian pacing in an intact dog
heart. (A) Lead II surface ECG temporally aligned with (B) a
bipolar mapping catheter positioned on the His bundle. (C) The ECG
during pacing (arrows) with 13 mA shows three captured beats with
wide QRS complexes and one sinus beat. (D) The ECG shows a sinus
beat followed by three narrow complex QRS paced beats (arrows show
20 mA pacing artifact) during His bundle capture.
[0037] FIG. 15 is a photograph of the experimental rabbit heart
showing the anatomical landmarks and the impalement sites. CS,
coronary sinus; AVN, atrioventricular node; His, His bundle; RA,
right atrium; VS, ventricular septum. Green dot indicates the
recording site of the bipolar electrode. Action potentials were
recorded from the His bundle (blue dot) and endocardium (red dot),
respectively.
[0038] FIG. 16 is a graphical illustration of an example of the
pseudo ECG (A), the bipolar electrogram (B) and microelectrode
recordings of the His bundle (C) and the adjacent working
myocardium (D). In the pseudo ECG panel, the first signal (black
arrowed) is P wave and the second one (red arrow) is QRS wave.
Panel B is the derivatives of the bipolar electrogram signals. The
first and third deflections in panel B are temporally aligned with
the P and QRS wave in panel A and the second deflection (green
arrow) is the His bundle signal.
[0039] FIG. 17 illustrates a decremented-pacing protocol for
measuring restitution properties. The initial interval was 300 ms
and was decremented to 260 ms by 20-ms steps. Below 260 ms, it was
reduced in 10-ms steps to the target interval, and thereafter kept
at the target interval for 30 beats. Each cycle length was in
ms.
[0040] FIG. 18 is a scatterplot of ADP versus DI with fitted lines.
The blue dots and line denote the data points and the fitted line
for the His group, and the red dots and lines for the Endo
group.
[0041] FIG. 19 is a boxplot of AUC. The blue boxplot is for the His
group, and the red one is for the Endo group.
[0042] FIG. 20 illustrates action potential duration alternans
continuously recorded in the His bundle (A) and 2:1 block in the
adjacent working myocardium (B) at the cycle length of 130 ms
pacing from the His bundle. The spikes in the recordings are the
pacing artifacts. In panel A, the APD90 of the His bundle
alternated in a long-short pattern. The long APDs ranged from 111.8
ms to 113.6 ms, while the short ones ranged from 97.1 ms to 98.5
ms. The working myocardium lost one to one capture when the His
bundle had alternans.
[0043] FIG. 21 illustrates action potential durations (APD90)
during dynamic pacing in the His bundle (blue dots and curves) and
working myocardium (red dots and curves). As cycle length
progressively shortened, a transition from 1:1 capture to 2:1 block
with alternation between long and short action potentials
occurred.
DETAILED DESCRIPTION
[0044] Before any embodiments of the invention are explained in
detail, it is to be understood that the invention is not limited in
its application to the details of construction and the arrangement
of components set forth in the following description or illustrated
in the following drawings. The invention is capable of other
embodiments and of being practiced or of being carried out in
various ways.
[0045] Also, it is to be understood that the phraseology and
terminology used herein is for the purpose of description and
should not be regarded as limiting. The use of "including,"
"comprising" or "having" and variations thereof herein is meant to
encompass the items listed thereafter and equivalents thereof as
well as additional items. The terms "mounted," "connected" and
"coupled" are used broadly and encompass both direct and indirect
mounting, connecting and coupling. Further, "connected" and
"coupled" are not restricted to physical or mechanical connections
or couplings, and may include electrical connections or couplings,
whether direct or indirect. Also, electronic communications and
notifications may be performed using any known means including
direct connections, wireless connections, etc.
[0046] It should also be noted that a plurality of hardware and
software based devices, as well as a plurality of different
structural components, may be used to implement various embodiments
described herein. In addition, it should be understood that
embodiments may include hardware, software, and electronic
components or modules that, for purposes of discussion, may be
illustrated and described as if the majority of the components were
implemented solely in hardware. However, one of ordinary skill in
the art, and based on a reading of this detailed description, would
recognize that, in at least one embodiment, the electronic based
aspects may be implemented in software (e.g., stored on
non-transitory computer-readable medium) executable by one or more
processors. As such, it should be noted that a plurality of
hardware and software based devices, as well as a plurality of
different structural components may be utilized to implement
various embodiments. Furthermore, and as described in subsequent
paragraphs, the specific configurations illustrated in the drawings
are intended to exemplify embodiments and that other alternative
configurations are possible. For example, "controllers" described
in the specification can include standard processing components,
such as one or more processors, one or more computer-readable
medium modules, one or more input/output interfaces, and various
connections (e.g., a system bus) connecting the components. In some
instances, the controllers described in the specification may be
implemented in one of or a combination of a general processor, an
application specific integrated circuit (ASIC), a digital signal
processor (DSP), a field programmable gate array (FPGA),
combinational logic or state circuitry, or the like.
[0047] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art. In case of conflict, the present
document, including definitions, will control. Preferred methods
and materials are described below, although methods and materials
similar or equivalent to those described herein can be used in
practice or testing of the present invention. All publications,
patent applications, patents and other references mentioned herein
are hereby incorporated by reference in their entirety. The
materials, methods, and examples disclosed herein are illustrative
only and not intended to be limiting.
[0048] For the recitation of numeric ranges herein, each
intervening number there between with the same degree of precision
is explicitly contemplated. For example, for the range of 6-9, the
numbers 7 and 8 are contemplated in addition to 6 and 9, and for
the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6,
6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
[0049] "About" is used synonymously herein with the term
"approximately." Illustratively, the use of the term "about"
indicates that values slightly outside the cited values, namely,
plus or minus 10%. Such values are thus encompassed by the scope of
the claims reciting the terms "about" and "approximately."
[0050] The present disclosure provides a novel ICD for detecting
and terminating cardiac arrhythmias and method of using the same.
The device as described herein improves detection and treatment of
dangerous and life-threatening heart rhythms by delivering
real-time, customized low-energy pacing pulses to specific anatomy
in the heart. Additionally, the low-energy pacing pulses provide a
pain free treatment to the patient in contrast to conventional
large, mono-phasic or biphasic defibrillation shocks that are
typically painful for the patient.
[0051] FIGS. 1-6 illustrate an exemplary implantable cardioverter
defibrillator (ICD) 10 configured to detect and terminate
arrhythmias (e.g., ventricular fibrillation (VF), ventricular
tachycardia, etc.). The ICD 10 includes a housing 15 configured to
be implanted into a patient (e.g., within the thoracic cavity
remote spaced from the patient's heart) having one or more leads 20
extending from the housing into the interior of the heart H via one
or more veins. As described in greater detail below, the ICD 10 is
configured to execute a method in order to detect and treat VF
using low-energy pacing pulses delivered to the ventricular
specialized conduction system, e.g., His bundle, and propagated
through the ventricles via the Purkinje fibers in order to
terminate VF by rendering a critical mass of ventricular tissue
unexcitable by activation thereby terminating reentrant circuits
that perpetuate VF. Accordingly, normal sinus rhythm can be
restored using low-energy pacing pulses rather than conventional
large, mono-phasic or biphasic defibrillation shocks.
[0052] With reference to FIG. 1, the ICD 10 includes a lead 20
extending from the housing 15 to an electrode 25 coupled to the
ventricular specialized conduction system of the patient's heart.
The ventricular specialized conduction system includes the His
bundle, bundle branches, and the Purkinje system. More
particularly, in other embodiments, the electrode is coupled to the
His-bundle in the patient's heart. The ICD 10 also includes a
sensing lead extending from the housing 15 and into the heart for
sensing and detecting ventricular arrhythmias, in particular,
ventricular fibrillation. The sensing lead provides a signal to the
ICD for processing and determination of next steps as described
below.
[0053] In other embodiments, the ICD 10 may include two or more
leads 20 having corresponding electrodes. The additional leads may
include, but are not limited to, an additional His-bundle lead that
includes an electrode that is coupled to the His-bundle (i.e.,
another His-bundle electrode) within the patient's heart H, one or
more right atrial leads with an electrode that is coupled at a
point within the right atria or onto the myocardium of the right
atria (i.e., right atrial electrode), one or more right ventricular
leads with an electrode that is coupled at a point within the right
ventricle or onto the myocardium of the right ventricle (i.e.,
right ventricular electrode), one or more left atrial leads with an
electrode that is coupled at a point within the left atria or onto
the myocardium of the left atria (i.e., left atrial electrode), and
one or more left ventricular leads with an electrode that is
coupled at a point within the left ventricle or onto the myocardium
of the left ventricle (i.e., right atrial electrode).
[0054] FIG. 2 illustrates an exemplary block diagram of the ICD 10.
As illustrated, the ICD 10 includes a plurality of electrical and
electronic components that provide power, operational control, and
protection to the components and modules within the device. The ICD
10 includes a power supply 30 (e.g., a battery) for powering a
controller 35 having a memory 40, an electronic processor 45, a
pulse generator 50, a detector circuit 55, coupled by a bus 60. The
ICD 10 also includes a capacitor circuit 65 for delivering a
defibrillation shock to the heart H or cardiac tissue. The device
10 may also include additional or alternative components, including
additional electronic processors and memory, or application
specific integrated circuits (ASICs).
[0055] The controller 35 executes software, which may be stored in
the memory 40, via the electronic processor 45 to carry out the
functionalities of the ICD 10. The electronic processor 45 is
communicatively coupled to the memory 40 and executes instructions
stored on the memory 40. The electronic processor 45 is configured
to retrieve from the memory 40 and execute, among other things,
instructions related to the control processes and methods described
below.
[0056] The memory 40 stores program instructions and data. The
memory 40 may include, for example, a program storage area and a
data storage area. The program storage area and the data storage
area may include combinations of different types of memory, such as
read-only memory ("ROM"), random access memory ("RAM") (e.g.,
dynamic RAM ["DRAM"], synchronous DRAM ["SDRAM"], etc.),
electrically erasable programmable read-only memory ("EEPROM"),
flash memory, or other suitable magnetic, optical, physical, or
electronic memory devices.
[0057] The pulse generator 50 and the detector circuit 55 are each
coupled to the electronic processor 45 and an input/output port 70
configured to receive the His-bundle lead 25 such that the pulse
generator 50 and detector circuit 55 are in electrical
communication with the His-bundle electrode 25. In other
embodiments, the pulse generator 50 and the detector circuit 55 may
be coupled to additional data input/output ports 70 that are
configured to receive the additional leads described above such
that the pulse generator 50 and the detector circuit 55 are in
electrical communication with the corresponding electrodes of the
leads.
[0058] The pulse generator 50 may be any suitable electronic
circuit, ASIC, etc. configured to provide electrical pulses having
specific characteristics (e.g., pulse frequency, pulse duration,
pulse voltage, pulse current, etc.). The detector circuit 55 may be
any suitable circuit, ASIC, hardware, or software configured to
obtain, detect, and/or pre-process electrical signals from the
heart provided by the sensing wire 22. In addition, the detector
circuit 55 may be embodied in software, executable by the
electronic processor 45, for the functions described herein.
[0059] In some embodiments, the ICD 10 further includes a
communication module (e.g., a transceiver) that couples the ICD to
a peripheral device (e.g., a server, computer, tablet, smartphone,
etc.) via a communication link to enable the controller to
communicate with the peripheral device. The communication link may
include one or more wired or wireless connections, networks, and
protocols including, but not limited to a local area network (LAN),
the Internet, Wi-Fi, cellular, LTE, 3G, Bluetooth, Ethernet, USB,
and the like. In one example, the communication module may allow a
user to access or update software stored in the memory via data
transmitted from a peripheral device to the communication module.
In another example, the controller may be configured to send data
gathered by the electronic processor and stored in the memory via
the communication module for peripheral processing and
analysis.
[0060] FIG. 3A is a flow chart illustrating a method for treating a
cardiac arrhythmia. The method includes the controller 35 sampling
electrical signals (via the sensing lead) propagating through the
heart (step 100) to determine whether or not an arrhythmia, such as
VF or VT is present based on the sample electrical signal. If a
cardiac arrhythmia is present in the sample electrical signal, the
controller 35 executes (at step 104) an algorithm for the signal to
determine a cycle length of the arrhythmia and a set of pacing
pulse characteristics for the arrhythmia. The cycle length of the
arrhythmia can be determined via known software methodology that
resides in existing ICDs. In addition (at step 108), a
defibrillation capacitor 65 in the ICD 10 is charged for a period
of time (e.g., 10 seconds). Based on the cycle length of the
arrhythmia, the controller 35 generates a defibrillation pulse
signal, which is subsequently communicated to the pulse generator
50 to generate and transmit the defibrillation pulse signal to the
His-bundle electrode 25 via the His-bundle lead 20 (step 112) to
accomplish defibrillation. For example, the pulse generator 50 can
deliver 5-30 pacing pulses to the His-bundle at 50-105% of the
cycle length of the arrhythmia. As another example, the pulse
generator 50 can deliver 10-25 pacing pulses to the His-bundle at
80-105% of the cycle length of the arrhythmia. The pulse generator
50 then slows (at step 116) the delivery of the pacing pulses of
the cycle length to the sinus rate. The controller 35 again samples
(at step 120) electrical signals propagating through the heart to
determine whether or not an arrhythmia, such as VF or VT is present
based on the sample electrical signal. If the cardiac arrhythmia is
still present, the controller 35 transmits (at 124) a signal to the
capacitor circuit 65 to deliver a defibrillation shock to the
cardiac tissue. If the cardiac arrhythmia is no longer present in
the sample electrical signal, the controller 35 transmits (at 128)
a signal to the capacitor circuit 65 to discharge the capacitor. It
is noted that these low energy cardioversion techniques (e.g., with
the parameters noted above) delivered directly to the His-bundle to
capture the Purkinje system have not previously been shown to be
effective in halting VF.
[0061] FIG. 3B illustrates one method for detecting and terminating
ventricular arrhythmias using the ICD 10. The method includes
sampling electrical signals propagating through the heart (step
200), determining whether or not VF is present based on the sample
electrical signal (step 204), and determining whether or not VT is
present based on the sample electrical signal (step 208). If VF is
present in the sample electrical signal, the controller 35 executes
(at step 212) a VF characteristic algorithm to the signal to
determine a set of pacing pulse characteristics for a
defibrillation signal, which is subsequently communicated to the
pulse generator 50 to generate and transmit the defibrillation
pulse signal to the His-bundle electrode 25 via the His-bundle lead
20 (step 216) to accomplish defibrillation. After defibrillation,
the ICD 10 returns to step 200. If VF is not present in the sample
electrical signal, but VT is present, the controller 35 is
configured to communicate conventional ATP signal characteristics
to the pulse generator 50, which subsequently generates and
transmits an ATP signal to the His-bundle electrode 25 via the
His-bundle lead 20 (step 220). If neither VF nor VT is present in
the sample electrical signal, the controller 35 continues to
continuous or timed repetition of step 200 (i.e., sampling of the
electrical signals propagating through the heart). In addition, it
should be apparent that VT may be present or induced by the
defibrillation signal, making ATP necessary after defibrillation in
order to recapture normal sinus rhythm.
[0062] The sampling accomplished in step 200 more specifically
includes operating the ICD 10 to sample the electrical signals
propagating through the heart H. The sample electrical signal is
gathered, for example, as a change in voltage at the His-bundle
electrode over time that is pre-processed by the detector circuit
55 and delivered to the electronic processor 45. Subsequently, the
sample electrical signals are processed by the electronic processor
45 to determine intrinsic characteristics of the heart H over time
such as heart rate/cycle length, and rate comparison (i.e., rate of
the ventricles compared to the rate of the atria), among others.
The intrinsic characteristics may be stored to the memory 40 to
create a record of heart functionality. Subsequently, the
electronic processor 45 evaluates the intrinsic characteristics to
determine whether the sample electrical signals are indicative of
VF or VT. For example, the electronic processor 45 may make a
comparison of the signal to known VF or VT patterns stored in the
memory 40 to determine if ventricular fibrillation is present.
[0063] With reference to FIG. 4, step 212 more specifically
includes executing, via the electronic processor 45, a VF
characteristic algorithm that is stored in the memory to determine
a time based VF characteristic (e.g., ventricular fibrillation
cycle length, ventricular fibrillation cycle rate, etc.) after VF
is detected in step 204. In the illustrated embodiment, the VF
characteristic algorithm includes receiving a sample VF electrical
signal, taking (at step 224) a temporal derivative of the sample VF
electrical signal, determining (at step 228) the maximum negative
downslope during a training period having a predetermined length,
and calculating (at step 232) the average VF cycle length during a
number of consecutive activations that reach 40% of the maximum
negative downslope during the training period. Accordingly, the VF
characteristic algorithm uses the sample VF electrical signal to
determine an average VF cycle length. Alternatively, other
algorithms for determining average VF cycle length, or other VF
time based characteristics, may be employed.
[0064] With reference to FIG. 5, step 232 more specifically
includes executing, via the electronic processor 45, a VF treatment
algorithm to determine (at step 236) a set of pacing pulse
characteristics (e.g., number of pulses, pulse duration, cycle
length, current, voltage, etc.) for the defibrillation signal based
on the average VF cycle length. In the illustrated embodiment, the
set of pacing pulse characteristics may set a pacing pulse cycle
length that is between approximately 50-105% of the VF cycle
length. More specifically, the pacing pulse cycle length may be
approximately 90% of the VF cycle length. In this example, the
number of pulses, pulse duration, pulse voltage, and pulse current
may be predetermined values (e.g., based on patient
characteristics, etc.) or functions (e.g., successively
increasing/decreasing pulse duration or pulse voltage, etc.).
However, the number of pulses, the pulse duration, pulse voltage,
and pulse current may also be varied based on the VF cycle length.
In addition, when other VF time-based characteristics determined in
the method, the set of pacing pulse characteristics may be either
varied or set as predetermined values.
[0065] With continued reference to FIG. 5, the controller 35
subsequently communicates (at step 240) the defibrillation signal
to the pulse generator 50, which in turn generates and transmits
(at step 244) the defibrillation signal to the His-bundle electrode
25 via the His-bundle lead 20 using power from the power supply
30.
[0066] Step 208 more specifically includes communicating the ATP
signal characteristics from the controller 35 to the pulse
generator 50 after VT is detected. The pulse generator 50 then
generates and transmits an ATP signal to the His-bundle electrode
25 via the His-bundle lead 20.
[0067] In operation, the ICD 10 detects and terminates arrhythmias
(e.g., according to the methods of FIGS. 3A and 3B). The ICD 10
monitors electrical activity within the heart H to detect the
presence of VF and VT, and subsequently delivers a treatment upon
detection. When VF is detected, the ICD 10 delivers the
defibrillation signal in order to terminate VF. In the example
described above, the defibrillation signal includes a set of pacing
pulse characteristics having the pacing pulse cycle length that is
between approximately 70-98% of the sampled VF cycle length.
Delivery of this defibrillation signal to the His-bundle via the
His bundle electrode 25, which is illustrated in the exemplary
waveform of FIG. 6, has specific physiological implications for
terminating VF.
[0068] Delivery of the defibrillation signal to the His-bundle
results in the electrical signal being propagated through the
ventricles via the Purkinje fibers. When delivered at the pacing
pulse cycle length, each successive pulse's propagation through the
ventricles results in recapture of increasing amounts of
synchronous depolarization of successive portions of cardiac tissue
prior to improper, asynchronous depolarization of portions of
ventricular tissue due to fibrillation. Once a critical mass of
cardiac tissue is captured and depolarization is propagated
properly through the critical mass of cardiac tissue, fibrillation
is considered to be terminated and the ventricles will contract
such that blood flow is restored.
[0069] In some cases, such as the exemplary waveform illustrated in
FIG. 6, VT is induced or occurs after defibrillation. Accordingly,
after defibrillation is accomplished, VT is detected resulting in
the application of ATP to terminate VT and restore sinus
rhythm.
[0070] Advantageously, the stepwise recapture of cardiac tissue via
the Purkinje fiber conduction pathway obviates the necessity for a
high magnitude shock in order to terminate fibrillation. The pacing
pulse cycle and each pulse's subsequent propagation through the
His-bundle significantly decrease the energy required to accomplish
defibrillation. This results in decreased cardiac tissue morbidity
due to high magnitude shocks, decreased pain experienced by
patients during defibrillation, a reduction in anxiety associated
with prior ICD's defibrillation techniques, and an overall increase
in ICD patients' quality of life.
EXAMPLES
[0071] The overall goal is to combine three new concepts and
techniques into a clinically relevant method for low energy
defibrillation. As discussed above, the key concepts that have
formed embodiments of the invention are: 1) low energy multi-pulse
defibrillation techniques have demonstrated the feasibility of
substantial reductions in shock energy in simulations and small
hearts, 2) the Purkinje system plays an active role in the
maintenance of VF and in defibrillation shock failure, and 3)
development of methods for directly pacing the Purkinje system with
clinically relevant, permanent leads. The combination of these
three independent breakthroughs will lead to significant reductions
in DFTs.
Example 1: The Purkinje System can Operate as a Pacing Distribution
System During VF Such that Cardiac Activation May Spread Through
the Conduction System and Capture Sufficient Cardiac Mass Such that
VF Wavefronts are Halted
[0072] This approach has the potential to reduce DFTs to a series
of pacing level amplitude shocks. This approach is fundamentally
different from traditional defibrillation mechanisms. Effective
defibrillation therapy has been based on the principle that large
shocks not only directly stimulate tissue near the shocking
electrodes, but that virtual electrode effects cause secondary
sources at sites far from the shocking electrodes. Substantial
reductions in defibrillation energy are unlikely to be achieved
while the primary mechanism for defibrillation is the creation of
secondary sources far from stimulating electrodes. Since this
technique is based on local capture and spread of activation
through the conduction system rather than creation of far field
secondary sources, the stimulation energy requirements will be
comparable to pacing-level energies, which are well tolerated by
patients and do not result in cardiac damage. This may result in
orders of magnitude reductions in defibrillation energy, thereby
resulting in damage free, painless defibrillation that can be
performed with current pacemaker and ICD technology.
[0073] Since the intended treatment population for this technology
is patients with ICDs, the techniques were developed and
demonstrated first in normal rabbit and dog hearts, but then will
also be tested in infarcted rabbit hearts with heart failure (HF)
and in dogs with HF and cardiomyopathy.
[0074] Many animal models of HF are available, each with strengths
and weaknesses. For testing the proposed low energy cardioversion
techniques, several concerns are: 1) distribution and function of
the conduction system, 2) representative model of the ICD
population, and 3) feasibility of use within the budget and
capabilities available. As noted above, rabbits and dogs have a
similar Purkinje fiber distribution to humans. Patients with ICDs
have compromised LVEF, often with ischemic heart disease and
dilated cardiomyopathy. For these reasons, both a rabbit ischemic
HF model and a canine rapid ventricular paced HF model will be
utilized. While these models do not represent all ICD patients, the
combination of these two models represents a large contingent of
ICD patients.
[0075] While dogs, sheep, and pigs have been used for rapidly paced
dilated cardiomyopathy, dogs offer the most similar conduction
system to humans and have been well characterized. The inventors
have extensive experience with chronic pacing AF models and have
implanted and tracked approximately 50 dog and goat animals in AF.
Even with beta-blockers to slow the ventricular response rate, dogs
undergoing rapid atrial pacing develop LV dysfunction and HF (LVEF
decreased from 54% at baseline to 33% after 6 months of AF). As a
pilot study, RV leads were implanted and RV pacing was conducted at
240 beats per minute for 3 weeks followed by 220 beats per minute
and achieved significant HF in a goat model. These goats developed
enlarged hearts and compromised EF, consistent with dilated
cardiomyopathy.
[0076] In order to utilize the Purkinje system as a pacing
distribution system in VF, the Purkinje system must have an
excitable gap, as does the working myocardium. At normal sinus
heart rates, the Purkinje system has a longer APD and thus longer
refractory period than the working myocardium. However, under rapid
pacing rates, the APD and refractory periods of the Purkinje system
accommodate to the rapid rates such that Purkinje fibers have the
same or shorter APDs and refractory periods than
cardiomyocytes.
[0077] The His bundle, bundle branches, and even many of the
proximal Purkinje fibers are electrically isolated from the
underlying myocardium. The more rapid conduction velocity of the
Purkinje system (1.5-4 m/s) compared to the working myocardium
(0.3-0.5 m/s) combined with the lack of electrical continuity with
the underlying myocardium would suggest that large sections of the
His-Purkinje system should activate synchronously during VF. It was
previously demonstrated that the Purkinje system is an interactive
player in the re-entrant and focal activity that occurs during VF
and during defibrillation.
[0078] Myocardial ischemia has been shown to affect APD and
post-repolarization refractoriness. An excitable gap in normal
conduction tissue and myocardium may not indicate that the same
will be true in chronic infarct tissue. There is often a layer of
subendocardial sparing associated with infarct, and the
excitability of this tissue is unknown compared to the surrounding
tissue during VF.
[0079] In a first study, rabbit hearts were excised, perfused, and
opened. An incision was made through the anterior RV and through
the anterior septum to expose the LV endocardium. A rigid plastic
ring attached to a rod was sutured over the high left bundle branch
(LBB) on the LV septum. The ring was held in place to minimize
motion of the tissue under the ring. A bipolar electrode on a
micromanipulator was used to identify the LBB bundle and was used
to directly pace the His bundle. Floating microelectrodes were used
to impale the LBB as well as the adjacent ventricular working
myocardium. VF was induced electrically and allowed to stabilize in
the perfused heart for 30 seconds. This simulated early VF and
minimized the time effect as global ischemia set in in an
unperfused VF model. Action potential duration (APD) and diastolic
interval (DI) were quantified for the LBB and adjacent working
myocardium. The VF activation rate of the LBB was determined, and
pacing pulses were delivered from the electrode set closest to the
Purkinje fiber impalement site for 2 seconds at the VF cycle
length. Following a 10 second recovery period, trains lasting 2
seconds were delivered at 5% intervals below the VF cycle length
(at 95, 90, 85, . . . 55, 50% of the Purkinje fiber VF cycle
length), with 10 second recovery periods between tests.
Post-repolarization refractoriness and the excitable gap in the LBB
and working myocardium were determined by comparing minimum cycle
lengths that result in capture, action potential characteristics,
and coupling intervals to pacing pulses.
[0080] Preliminary studies demonstrate the ability to record
simultaneous microelectrode recordings from the endocardium of a
fibrillating heart (FIG. 8). While these recordings were obtained
in a dog heart with a microelectrode in a free running Purkinje
fiber and adjacent myocardium, the technique was similar for His
bundle and myocardial impalement in the rabbit heart.
[0081] An experiment was conducted with an isolated rabbit heart to
demonstrate the ability to perform real time rate detection and
pacing delivery. An analog input of a digital signal processor
microcontroller board (TMS320C5516 16 bit fixed point 100 MHz
process with a 24 bit ADC, Texas Instruments, Inc.) was used to
record an electrogram from a hook electrode on the LV epicardium of
an isolated and perfused rabbit heart. A pacing electrode
(approximately 3 mm from the sensing electrode) was inserted into
the LV free wall epicardium. The heart was put into fibrillation
with burst pacing. The microcontroller took the temporal derivative
of the sensing electrode, determined the maximum negative downslope
during a 4 second training period, calculated the average cycle
length during 13 consecutive activations that reached 40% of the
maximum negative downslope during the training period, and
delivered 10-50 pacing pulses at 90% of the average VF cycle
length. The pacing pulses were able to capture a section of
fibrillating myocardium in the vicinity of the pacing electrode
during VF (FIG. 9).
[0082] The ability to differentiate His bundle activation from the
working myocardium during VF was demonstrated. An 8.times.8 array
with 0.6 mm spacing was placed over the His bundle and sinus and VF
were recorded. While the unipolar recordings were sufficient to
identify His-bundle activations during sinus rhythm, bipolar and
Laplacian (4*center electrode--N, S, E, W electrodes) electrograms
reduced far field signals and improved local signal detection
(FIGS. 10-11). With the Laplacian electrograms, Ventricular,
His-bundle, and atrial activations could easily be distinguished
during VF.
[0083] In an isolated rabbit heart, the His bundle was identified
as in FIG. 12. A second array was placed on the RV septal
endocardium in a region approximately 1-2 cm from the His bundle
array. Perfused VF was induced electrically, and then pacing pulses
were delivered to the His bundle at 95% of the intrinsic His-bundle
activation rate. Pacing at 2 mA captured the His bundle near the
pacing site as well as Purkinje and myocardial tissue 1-2 cm from
the His site (see FIG. 12). This experiment demonstrated that 1) an
excitable gap exists in the Purkinje system during VF, and 2)
pacing can capture not only the local His, but that the paced
impulse can travel to sites distant from the paced site through the
conduction system during VF.
Example 2: Effective Pacing Parameters for Terminating VF Through
Pacing of the His-Purkinje System
[0084] Multi-pulse defibrillation techniques that deliver stimuli
near the VF cycle length rely on progressive capture of increasing
amounts of tissue with a train of pulses. Low energy multi-pulse
defibrillation techniques may be effective in large hearts if one
or more of the following criteria are met: 1) pulses are of
sufficient strength to cause virtual electrodes at sites distant
from the stimulation electrodes, 2) pulses are delivered at
strategic locations such that stable reentrant circuit sites are
disrupted and the pacing pulses can dominate the activity of the
heart, or 3) excitation pulses are distributed throughout much of
the heart such that tissue captured adjacent to electrodes sums to
a critical mass of the heart and extinguishes activity throughout
the heart. Criteria 1 is utilized by clinically accepted
defibrillation techniques. Very large shocks are almost always
nearly successful in terminating fibrillation, but due to reasons
outlined earlier, reductions in defibrillation thresholds would
lead to less pain, damage, and device longevity. Criteria 2 has
proven to be problematic because there does not seem to be a
consensus as to critical anatomical or functional locations that
would be consistent, predictable targets for stable reentrant
circuits. Criteria 3 would either require a very large number of
electrodes throughout much of the heart, which would not be
clinically acceptable, or utilization of the specialized conduction
system to spread activation pulses through much of the heart in a
nearly synchronously. Embodiments of the invention utilize the
ventricular specialized conduction system of the heart to
distribute pacing pulses through a large area of the heart to
capture a critical mass of the heart and to thereby terminate
VF.
[0085] As noted above, several different multi-pulse algorithms
have been published. High frequency AC techniques are likely to
rely on direct stimulation of the tissue to cause conduction block.
An alternative technique is based on the same principles used to
pace sections of the myocardium during fibrillation. These
techniques typically involve calculating the mean VF cycle length
and then delivering pacing pulses at or just below the VF cycle
length. Pacing at 95% of the VF cycle length captured a mean of 3.8
cm.sup.2 of the epicardium in a pig VF model. The region of tissue
captured by pacing increased in size until the stimulus current
reached approximately 10 times the diastolic pacing threshold.
Anti-tachycardia pacing, which delivers a series of pacing pulses
at a cycle length shorter than the inherent cycle length of
ventricular tachycardia, is often successful at stopping
tachycardia, but rarely terminates VF. It is noted that these
studies have not applied these techniques to the His bundle or the
ventricular specialized conduction system of the heart. In the
studies, these techniques have not been applied to the His bundle
because research published by the inventors' labs has only recently
led to understanding the important role that the His-Purkinje
system plays in VF maintenance. The inventors of this pioneering
work in identifying the critical role of the specialized
ventricular conduction system led to the innovative approach of
interfacing the His-Purkinje system directly to distribute
critically timed pulses to the rest of the myocardial tissue. Also,
until recently, there has not been a clinically relevant method for
interfacing the His bundle directly. However, with the emergence of
techniques for placing a permanent His bundle electrode for
resynchronization and pacing therapy gaining traction in the
cardiac electrophysiology community and with our unique
understanding of the His-Purkinje system in VF, this novel approach
was developed for low energy and pain free termination of VF.
[0086] Since a single electrode can effectively capture a section
of tissue, multiple electrodes have been used to attempt to capture
a broader region of tissue. Four pacing electrodes configured to
pace during the excitable gap on the surface of an isolated rabbit
heart successfully defibrillated the heart in 16% of VF episodes.
Simulations have recommended optimal spacing and timing of pacing
pulses through multiple electrodes. Little interest in placing
electrodes throughout the heart has blunted interest in this
technique.
[0087] A multistage defibrillation approach has been shown to lower
defibrillation energy requirements. A first phase consisting of
relatively large monophasic or biphasic shocks is thought to unpin
wavefronts in fibrillation. The second phase of medium amplitude
shocks prevents wavefronts from repining. The third phase is
essentially ATP and is thought to annihilate any remaining
wavefronts. Investigators have used this multiphase approach to
terminate VT and atrial fibrillation in a canine model. Recent
studies have shown that multistage defibrillation trains lowered
the AF DFT from 1.48 J to a cumulative 0.16 J in rapid atrial
pacing induced AF dogs when comparing standard biphasic shocks to
multistage defibrillation, respectively.
[0088] Recent modeling work has sought to determine the most
effective parameters for multistage defibrillation techniques. A
high resolution MM scan was used to reconstruct a model of a rabbit
RV. Sustained VF was established and shocks from far-field
electrodes were simulated. Stimuli were delivered at 16% and 88% of
the VF cycle length. Pulses delivered at 88% of the VF cycle length
were more effective than those delivered at 16%. VF was regularly
converted to either sinus rhythm or VT at 0.58% of the energy that
was required with single defibrillation shocks. Further reductions
in energy were achieved when VF was converted to VT and ATP pacing
was employed. In this simulation, stimuli delivered at 88% of the
VF cycle length terminated VF with only 2-3 times the diastolic
activation threshold.
[0089] Low energy multi-pulse defibrillation techniques have been
shown to be effective in small animal models and simulation, but
efficacy in treating large animals in VF has not been published.
This is likely due to the inability of the small shocks to create
virtual electrodes at sites far from the pacing site. Low energy
multi-pulse defibrillation therapy has been delivered through
standard pacing electrodes placed in the RV endocardial apex, on
the LV epicardium through CRT leads in the cardiac venous system,
or in open chest models with multiple electrodes placed on the
ventricular epicardium, but clinically relevant lead placement is
highly limited in both location and number of electrodes. Local
pacing may capture several cm.sup.2 of tissue during VF, which may
be sufficient to terminate VF in a small heart, such as a rabbit or
guinea pig heart, but this is not sufficient to terminate VF in a
large heart such as a dog, pig, or human heart.
[0090] Previous work has demonstrated that wavefronts in the
Purkinje system during VF may be large and that myocardial
activation is often initiated by wavefronts in the Purkinje system.
Since the conduction velocity is much faster in the Purkinje system
than in the working myocardium, the pacing pulses spread throughout
a much larger region during the excitable gap than they did in
working myocardial cells. Pacing at the His bundle lead to rapidly
spreading excitation wavefronts that progressively captured larger
and larger sections of the working myocardium throughout the
ventricular mass.
[0091] Many patients with an ICD have dilated cardiomyopathy and
HF. Ion channel remodeling, increased fibrosis, increased
myocardial mass, electrical remodeling, and other effects may
change the Purkinje-myocardial coupling or VF characteristics.
Therefore, the experiments were conducted in both normal hearts and
rapid paced dilated cardiomyopathy HF dog hearts to determine if
these changes affect the efficacy of direct His-Purkinje
pacing.
[0092] Experiments were conducted in three isolated rabbit hearts
in which an 8.times.8 array was placed over the His bundle while
another 4.times.4 array was placed on the RV free wall endocardium.
The His bundle signal was input into a microcontroller (see FIG.
9), and pacing pulses were delivered at 90% of the His VF cycle
length (see FIG. 13). In early VF, pacing did not result in
capture. After pacing for 20 cycles, 1:1 capture of the His,
Purkinje, and working myocardium was achieved. Upon termination of
pacing, VF was terminated. This effect was achieved in three rabbit
experiments. While regional capture was observed with epicardial
pacing in two experiments (see FIG. 9), VF was not terminated with
the termination of pacing. These promising experiments demonstrate
evidence that His-Purkinje pacing during VF may be an effective
treatment for VF cardioversion where ATP pacing of the ventricular
myocardium is ineffective.
Example 3: Technique for Delivering Low-Energy Pacing Trains to the
Purkinje System During VF to Terminate Fibrillation
[0093] Direct pacing of the Purkinje system has proven difficult
until recent improvements in steerable sheaths and catheters have
become available. The Select Secure 3830 ventricular lead and the
Select Site deflectable sheath (Medtronic, Inc.) is gaining
acceptance as a feasible catheter for chronic His bundle pacing.
While this approach has not been used for defibrillation, His
bundle pacing has led to improved ventricular synchrony and cardiac
output than patients with biventricular cardiac resynchronization
therapy.
[0094] Algorithms for detection of tachycardia cycle lengths and
ATP protocols are a standard feature in commercially available
ICDs. Incorporation of multi-pulse or high frequency pulse trains
to commercial devices likely will not require significant changes
to hardware. The addition of a His-bundle lead to current ICDs may
be accomplished by current CRT devices with a His-bundle pacing
lead in place of a left ventricular lead.
[0095] As discussed previously, ICD patients with HF and associated
pathologies may affect the efficacy of His-Purkinje pacing during
VF.
Example 4
[0096] Ventricular fibrillation (VF) is an important cause of
sudden cardiac death (SCD), which is responsible for approximately
half of cardiac mortality. Implantable cardioverter defibrillators
(ICDs) are now an established therapy for fatal ventricular
tachyarrhythmia. However, large shocks may cause tissue damage and
increase the risk of death. Thus, numerous defibrillation
techniques have been studied to lower the energy required for
cardioversion.
[0097] Some published studies have demonstrated that the Purkinje
system (PS) is an important driver of VF activation in the
maintenance of long duration VF (LDVF) (VF>2 min). PS activity
was present in 84% of fibrillatory wave fronts during induced VF in
dog isolated hearts and was responsible for driving the rapid
activation rate during LDVF. Also, the PS has the same or shorter
action potential duration (APD) and refractory periods than
cardiomyocytes under rapid pacing rates, which suggests that the PS
may have an excitable gap during VF. Thus, it is likely that
appropriately timed pacing pulses in the PS can conduct through
Purkinje-muscular junction (PMJ) and capture a large region of the
working myocardium (WM) in VF. There have been modeling and small
animal heart studies that suggest that stimulating PS during
arrhythmias may lead to termination of the arrhythmias or reduction
in energy required for termination. However, there has been lack of
a clinically relevant method for stimulating PS in vivo.
[0098] Recently, a study was published that also has shown that
during prolonged VF, the His bundle exhibits similar activation
patterns as the PS. This suggests that the His and the PS remain
electrically linked during VF and that pacing and capture of His
may lead to capture of the PS during VF. However it is unclear
whether the APD and refractory periods of the His have the similar
electrophysiological properties with the Purkinje fibers that can
be used as a target for interventional therapy.
[0099] Nine New Zealand white rabbits (weight of 2-4 kg) of either
sex were anesthetized using intramuscular injections of 30 mg/kg
ketamine and 5 mg/kg xylazine, followed by intravenous injections
of 10 mg/kg ketamine, 3 mg/kg xylazine and 500 IU of heparin. After
a median sternotomy, the hearts were excised and isolated rapidly
in 4.degree. C. Tyrode's solution, and then were
Langendorff-perfused with 37.degree. C. Tyrode's solution. The
perfusion pressure was maintained at 60 to 70 mmHg. The hearts were
also superfused by warm Tyrode's solution, with temperature
maintained at 37.+-.0.5.degree. C. The composition of Tyrode's
solution (in mM) was 130 NaCl, 1.2 NaH2PO4, 1 MgCl2, 4 KCl, 1.8
CaCl2, 24 NaHCO.sub.3, 11.2 Glucose, and 0.04 g/L bovine albumin
and it was oxygenated with O2 and CO2 to maintain a pH of
7.4.+-.0.05. The excitation-contraction uncoupler Blebbistatin (10
mM/L; Calbiochem.RTM., EMD Biosciences, Inc. La Jolla, Calif.) was
added to Tyrode's solution to suppress motion artifacts in the
recordings.
[0100] The right atrium was removed to expose the high right
ventricular septum and His, as shown in FIG. 15. A bipolar
electrode was placed on the His for signal discrimination and
pacing. Two standard glass microelectrodes (tip resistance, 1 to 5
M.OMEGA., filled with 3 mol/L KCl) were used to record the
intracellular action potential (AP) from the His and the right
ventricular septal endocardium simultaneously. One microelectrode
impaled the His bundle within 2 mm of the bipolar electrode, which
was used to verify that the action potential (AP) aligned with the
His signal in the bipolar electrode. The other microelectrode
recorded the WM signal (Endo group) within 10 mm of the His
impalement site. An Ag--AgCl reference electrode for the
intracellular recording electrode was placed in the perfusate. APs
were recorded with DC coupling as the difference in voltage between
the intracellular microelectrode and the extracellular Ag--AgCl
reference electrode. The signals were acquired by an Axoclamp 900A
amplifier (Axon Instruments, USA). Also, another three electrodes
were placed in the perfusate to calculate pseudo-ECG. All the
signals were recorded and monitored in real time using
LabChart.RTM. software through a Powerlab 16/30 system (AD
Instruments, Colorado Springs, Colo., USA) (FIG. 16).
[0101] Electrical pulses of 0.2 ms duration and twice diastolic
threshold were delivered through the bipolar electrode placed on
the His. A steady-state pacing protocol used as in a previously
published study was used to determine the restitution
characteristics. The S1-S1 interval was initially 300 ms and was
progressively decreased to 260 ms by 20-ms steps, and then was
reduced in 10-ms steps to the target interval, and thereafter kept
at the target interval for 30 beats (FIG. 17). After finishing the
restitution curve, the same protocol was used to pace from the
ventricular apex to determine if capture of the WM was lost at the
same cycle length (CL) with the one paced from the His bundle.
[0102] The data were selected if there was a stable microelectrode
recording and the last 10 beats of the 30 beats at each pacing CL
were analyzed. The APD was measured using LabChart.RTM. software at
90% repolarization (APD90). The diastolic interval (DI) was defined
as the interval from the end of the repolarization time of the
previous beat to the activation time of the next beat. The
confirmative analysis focused on comparing if the relationship
between APD and DI are the same for the His bundle and working
myocardium. The non-linear relationship between APD and DI (ms) was
assumed to be as follows.
y=.alpha.-.beta.e.sup.-x/.tau. (1)
where y denotes the value of APD and x for the value of DI, and
.alpha., .beta. and .tau. are parameter coefficients being
estimated from the data. It was assumed that both His and Endo
shared the same parameters for .alpha., .beta. and .tau. in the
above nonlinear model (1) and fit a common-parameter model. Then,
the non-linear model was fit assuming that each of the parameters,
.alpha., .beta. and .tau., was different between the His and the
Endo group. A global F-test was used to examine if two models (the
model assuming common parameters and the model assuming different
parameters) were statistically significantly different from each
other. If the F-test indicated that the two models were
significantly different, then the relationship between APD and DI
(or between APD and CL) was significantly different across the two
(His and Endo) groups. The non-linear model was fit (1) again and
re-parametrized the model so that we can check which of the three
parameters (.alpha., .beta. and .tau.) were significantly different
between the His and Endo group. If any of the parameters were found
significantly different between the His and Endo group, a separate
coefficient for that parameter was estimated for the His and the
Endo group. Otherwise, if a parameter was found to be not
significantly different between the His and Endo group, the same
coefficient was used for that parameter for both groups. The final
model included the common parameter(s) and the separate
parameter(s) based on the above processes. If the global F-test
indicated that the difference between the common parameters model
and the separate parameters model was not significantly different
from each other, the relationship between APD and DI was the same
for the two groups, and the common parameter model was served as
the final model.
[0103] For the relationship between APD and CL, either a linear or
non-linear relationship was developed by previous studies. Hence, a
derived outcome was used, the area under the curve (AUC), for
comparing between groups. The AUC was calculated using the two-way
curve with APD on the y-axis and CL on the x-axis with the same
range of CL for all animals within His and Endo groups. The AUC was
calculated by summing up the areas of trapezoids generated by
projecting each data point of ADP and CL pair onto the x-axis (a
triangular shape was obtained for the area from point (0, 0) to the
pair of ADP and the minimal CL). Although AUCs are continuous
measurements, due to fact that the AUCs are not normally
distributed for both Endo and His groups a Wilcoxon signed rank
test was used for comparing AUCs between His and Endo groups.
[0104] All statistical analyses were performed using SAS (SAS Inc.,
Cary, N.C., USA) version 9.4. Test results with p-values <0.05
were considered as statistically significant.
[0105] FIG. 18 presents the scatterplot of APD versus DI for both
His and Endo groups with the fitted restitution curves. Both
common-parameter and separate-parameter models are fitted for APD
versus DI among the His and Endo groups. The global F-test
indicated that the two models are statistically significantly
different (p<0.000001). By examining each of the three
parameters in the non-linear model, it was discovered that only the
a parameter is significantly different between the two groups. The
expected difference is 31.21 (95% CI: 15.33 to 47.09, p<0.0001),
with the Endo groups having a larger value. Thus, the relationship
between APD and DI are different across His and Endo groups.
[0106] The Wilcoxon signed rank test was performed to compare the
paired AUCs between His and Endo group under the null hypothesis
that the AUCs under both groups are equal. At the 0.05 test level,
this null hypothesis was rejected (p=0.018) and it was concluded
that the Endo and His groups have statistically significantly
different AUCs that describe the relationship between APD and CL
(FIG. 19).
[0107] During dynamic pacing, as the target interval closed to the
CL where His or WM developed 2:1 block, the onset of APD alternans
usually occurred. The His alternans developed in 7 of the 9 animals
(77.8%). Among these seven animals that had His alternans, four
rabbits also displayed WM alternans. There was another one animal
(11.1%) that had only WM alternans with no His alternans. The His
alternans developed at an average CL of 134.2.+-.13.1 ms. Compared
with the His alternans, the WM alternans happened at longer CL
(148.3.+-.13.3 ms, p<0.05). Similar to alternans, 2:1 block also
developed at shorter CL in His than in WM (130.0.+-.10.0 vs.
145.6.+-.14.2 ms, P<0.01). Furthermore, it was discovered that
most alternans of His occurred when the WM had 2:1 block (9 out of
12, 75.0%). FIGS. 20 and 21 showed the APD90 during dynamic pacing
in His and WM from one animal. The WM had alternans and 2:1 block
at 150 ms and 120 ms respectively, while the alternans and 2:1
block of His happened at 120 ms and 110 ms respectively.
[0108] The main findings from this study are as follows: 1) The His
can be captured at shorter cycle lengths than the WM, 2) The APD of
the His is shorter than the APD of the WM, and 3) Alternans develop
in the His at short cycle lengths with His pacing when 2:1
conduction block occurs in the WM.
[0109] As mentioned previously, the PS plays a significant role as
a driver of the rapid activation rates of VF, particularly after
the first 2-3 minutes of VF. An excitable gap exists in the WM
during VF20 and the results of this study demonstrate that the APD
of His is shorter than that of the WM across a broad range of CLs.
This is consistent with the theory that an excitable gap may exist
in His during VF. For a pacing therapy to be successful at
capturing His and potentially to spread to the WM through the
specialized conduction system, an excitable gap in His would be
necessary.
[0110] Alternans have been shown to be related to conduction block
and potentially to arrhythmia onset. Because of the slow
propagation and long refractory period of the atrioventricular node
(AVN), alternans in the AVN node and phenomenon such as Winkebache
conduction through the AVN node are well documented. This may be
the first documentation of consistent alternans generation during
His bundle pacing. The results showed that the ventricular
alternans developed in longer CL than His alternans, which
suggested that the ventricle lost 1:1 capture in longer CL than the
His. In other words, when His had alternans, 2:1 block occurred in
the WM. As pacing CL decreased, calcium transient alternans may
happen, which will cause repolarization alternans in His. As a
result, the APD will alternate in a long-short pattern. For the
shorter AP in His, less current (the source) was generated, which
may be not sufficient enough to bring the adjacent repolarized
tissue (the sink) to its activation threshold, and propagation will
fail as the source-sink mismatch is too large. However, there is
another viewpoint that the alternans might be due to electrotonic
coupling with a nearby area showing 2:1 block, resulting in
"secondary" alternans. Strong electrical communication via gap
junction with other cells may cause a smoothing of the Ca2+ signal
over many cells, preventing alternans (voltage-Ca2+ feedback).
There are also some studies that demonstrated that partial gap
junction inhibition did have a strong effect on Ca2+ transient
alternans, significantly increasing the occurrence and intensity.
From these results, it was difficult to determine definitively the
relationship between the His alternas and ventricular 2:1 block.
Thus, further studies are needed to explore the mechanism of the
His alternans.
[0111] The APD of the His was significantly shorter than that of
the WM, which may provide the opportunity for delivering critically
timed pulses to the His and capturing both the specialized
conduction system and the WM to disrupt arrhythmias such as
ventricular tachycardia or ventricular fibrillation with short
cycle lengths.
[0112] Various features of the invention are set forth in the
following claims.
* * * * *